Biomedical subjects

Melvin E Andersen

Publications and source records attributed to Melvin E Andersen.

At least 37 records · Page 2Linked to original sources

PubMed2005

Pitfalls and related improvements of in vivo gas uptake pharmacokinetic experimental systems.

Gas uptake chamber studies have been widely used to study inhalation pharmacokinetics (PKs) in rodents, often for the ultimate purpose of developing physiologically-based pharmacokinetic (PBPK) models that can be used to describe human PKs and to support risk assessment for the chemical. In the course of our studies of gasoline PKs, we revisited several important issues heretofore not thoroughly addressed. Here, we report several refinements which will significantly improve future studies with this type of system, relating to the understanding of loss rates, the importance of carbon dioxide removal, and sampling of blood and chamber air at the same time. Losses of chemicals in gas uptake systems consist of leakage, adsorption to system components, and adsorption to the hair and skin (fur) of experimental animals. The loss rates were experimentally determined for a series of chemicals and mixtures including n-hexane, benzene, toluene, ethylbenzene, o-xylene, gasoline, and other gasoline components. The rate of loss to the animals' fur was similar to loss rates to system components and involved absorption to both hair and skin. Most of the absorption to fur was reversible when the chamber concentration was low enough. The amount of chemical that desorbed from the animal after an experiment was significant when compared to the amount of chemical in the chamber at the end of a gas uptake experiment, indicating that the rate of decline in concentrations can be influenced by a decrease in the fur absorption rate or desorption of chemicals. A modified gas uptake system design is described in which a steel ring improved the connections to an autosampler and allowed insertion of probes to monitor gases, such as carbon dioxide (CO2), in the chamber. When CO2 absorbent efficiency was inadequate, CO2 concentrations rose to levels that significantly affected the animals' ventilation rate. Using a real-time CO2 probe, an absorbent system was developed that adequately controlled CO2 levels in the chamber. Attention to details of absorptive loss and CO2 scrubbing can improve the reliability of kinetic constants inferred from closed chamber studies. We then describe a method for extending gas uptake experiments by simultaneously collecting blood to be analyzed for chemicals and/or metabolites.

Air Pollutants↗

PubMed2005

Evaluation of physiologically based pharmacokinetic models in risk assessment: an example with perchloroethylene.

One of the more problematic aspects of the application of physiologically based pharmacokinetic (PBPK) models in risk assessment is the question of whether the model has been adequately validated to provide confidence in the dose metrics calculated with it. A number of PBPK models have been developed for perchloroethylene (PCE), differing primarily in the parameters estimated for metabolism. All of the models provide reasonably accurate simulations of selected kinetic data for PCE in mice and humans and could thus be considered to be "validated" to some extent. However, quantitative estimates of PCE cancer risk are critically dependent on the prediction of the rate of metabolism at low environmental exposures. Recent data on the urinary excretion of trichloroacetic acid (TCA), the major metabolite of PCE, for human subjects exposed to lower concentrations than those used in previous studies, make it possible to compare the high- to low-dose extrapolation capability of the various published human models. The model of Gearhart et al., which is the only model to include a description of TCA kinetics, provided the closest predictions of the urinary excretion observed in these low-concentration exposures. Other models overestimated metabolite excretion in this study by 5- to 15-fold. A systematic discrepancy between model predictions and experimental data for the time course of the urinary excretion of TCA suggested a contribution from TCA formed by metabolism of PCE in the kidney and excreted directly into the urine. A modification of the model of Gearhart et al. to include metabolism of PCE to TCA in the kidney at 10% of the capacity of the liver, with direct excretion of the TCA formed in the kidney into the urine, markedly improved agreement with the experimental time-course data, without altering predictions of liver metabolism. This case study with PCE demonstrates the danger of relying on parent chemical kinetic data to validate a model that will be used for the prediction of metabolism.

Animals↗

PubMed2005

Evaluation of potential toxicity from co-exposure to three CNS depressants (toluene, ethylbenzene, and xylene) under resting and working conditions using PBPK modeling.

Under OSHA and American Conference of Governmental Industrial Hygienists (ACGIH) guidelines, the mixture formula (unity calculation) provides a method for evaluating exposures to mixtures of chemicals that cause similar toxicities. According to the formula, if exposures are reduced in proportion to the number of chemicals and their respective exposure limits, the overall exposure is acceptable. This approach assumes that responses are additive, which is not the case when pharmacokinetic interactions occur. To determine the validity of the additivity assumption, we performed unity calculations for a variety of exposures to toluene, ethylbenzene, and/or xylene using the concentration of each chemical in blood in the calculation instead of the inhaled concentration. The blood concentrations were predicted using a validated physiologically based pharmacokinetic (PBPK) model to allow exploration of a variety of exposure scenarios. In addition, the Occupational Safety and Health Administration and ACGIH occupational exposure limits were largely based on studies of humans or animals that were resting during exposure. The PBPK model was also used to determine the increased concentration of chemicals in the blood when employees were exercising or performing manual work. At rest, a modest overexposure occurs due to pharmacokinetic interactions when exposure is equal to levels where a unity calculation is 1.0 based on threshold limit values (TLVs). Under work load, however, internal exposure was 87%higher than provided by the TLVs. When exposures were controlled by a unity calculation based on permissible exposure limits (PELs), internal exposure was 2.9 and 4.6 times the exposures at the TLVs at rest and workload, respectively. If exposure was equal to PELs outright, internal exposure was 12.5 and 16 times the exposure at the TLVs at rest and workload, respectively. These analyses indicate the importance of (1) selecting appropriate exposure limits, (2) performing unity calculations, and (3) considering the effect of work load on internal doses, and they illustrate the utility of PBPK modeling in occupational health risk assessment.

Animals↗

PubMed2004

Dose-dependent transitions in mechanisms of toxicity.

Scientists and decision makers from all sectors agree that risk assessments should be based on the best available science. Several years ago, the Health and Environmental Sciences Institute (HESI), a global branch of the International Life Sciences Institute (ILSI), identified the need for better scientific understanding of dose-dependent transitions in mechanisms of toxicity as one avenue by which the best and latest science can be integrated into the decision making process. In July 2001, the HESI Project Committee on Dose-Dependent Transitions in Mechanisms of Toxicity established a group of academic, government, and industry scientists to engage in active technical discourse on the issue of dose-dependent transitions in mechanisms of toxicity. Over the next 18 months, case studies were examined. These case studies included acetaminophen, butadiene, ethylene glycol, formaldehyde, manganese, methylene chloride, the peroxisome proliferator-activated receptor, progesterone/hydroxyflutamide, propylene oxide, vinyl acetate, vinyl chloride, vinylidene chloride, and zinc (Slikker, W., Jr., Andersen, M.E., Bogdanffy, M.S., Bus, J.S., Cohen, S.D., Conolly, R.B., David, R.M., Doerrer, N.G., Dorman, D.C., Gaylor, D.W., Hattis, D., Rogers, J.M., Setzer, R.W., Swenberg, J.A., Wallace, K., 2004. Dose-dependent transitions in mechanisms of toxicity: case studies. Toxicol. Appl. Pharmacol. 201(3), 226-294 (this issue)). The HESI Project Committee sponsored two technical workshops in 2003. The first of these workshops took place on February 12-13, 2003, and was co-sponsored by the Agency for Toxic Substances and Disease Registry, the American Chemistry Council, the National Institute of Environmental Health Sciences, the Society of Toxicology, and the U.S. Environmental Protection Agency. Additional support was provided by Health Canada. Invited experts from government, academia, and industry provided scientific perspectives and recommendations at the workshop. The purpose of the workshop was to examine approaches to dose-response analysis, learn from the case study examples, and gather feedback from invited participants on the impact of dose-dependent transitions on the risk assessment process. The second forum consisted of a workshop in March 2003 at the Society of Toxicology Annual Meeting in Salt Lake City, UT. This paper addresses the issues discussed at both workshops, and presents the consensus conclusions drawn by expert participants.

Animals↗

PubMed2004

Dose-dependent transitions in mechanisms of toxicity: case studies.

Experience with dose response and mechanisms of toxicity has shown that multiple mechanisms may exist for a single agent along the continuum of the full dose-response curve. It is highly likely that critical, limiting steps in any given mechanistic pathway may become overwhelmed with increasing exposures, signaling the emergence of new modalities of toxic tissue injury at these higher doses. Therefore, dose-dependent transitions in principal mechanisms of toxicity may occur, and could have significant impact on the interpretation of reference data sets for risk assessment. To illustrate the existence of dose-dependent transitions in mechanisms of toxicity, a group of academic, government, and industry scientists, formed under the leadership of the ILSI Health and Environmental Sciences Institute (HESI), developed a series of case studies. These case studies included acetaminophen, butadiene, ethylene glycol, formaldehyde, manganese, methylene chloride, peroxisome proliferator-activated receptor (PPAR), progesterone/hydroxyflutamide, propylene oxide, vinyl acetate, vinyl chloride, vinylidene chloride, and zinc. The case studies formed the basis for technical discourse at two scientific workshops in 2003.

Acetaminophen↗

PubMed2004

Development of a physiologically based pharmacokinetic model for volatile fractions of gasoline using chemical lumping analysis.

Physiologically based pharmacokinetic (PBPK) models have often been used to describe the absorption, distribution, metabolism, and excretion of chemicals in animals but have been limited to single chemicals and simple mixtures due to the numerous parameters required in the models. To overcome the barrier to modeling more complex mixtures, we used a chemical lumping approach, used in the past in chemical engineering but not in pharmacokinetic modeling, in a rat PBPK model for gasoline hydrocarbons. Our previous gasoline model consisted of five individual components (benzene, toluene, ethylbenzene, xylene, and hexane) and a lumped chemical that included all remaining components of whole gasoline. Despite being comprised of hundreds of components, the lumped component could be described using a single set of chemical parameters that depended on the blend of gasoline. In the present study, we extend this approach to evaporative fractions of gasoline. The PBPK model described the pharmacokinetics of all of the volatility-weighted fractions of gasoline when differences in partitioning and metabolism between fractions were taken into account. Adjusting the ventilation rate parameter to account for respiratory depression at high exposures also allowed a much improved description of the data. At high exposure levels, gasoline components competitively inhibit each other's metabolism, and the model successfully accounted for binary interactions of this type, including between the lumped component and the five other chemicals. The model serves as a first example of how the engineering concept of chemical lumping can be used in pharmacokinetics.

Adsorption↗

PubMed2004

Ethyl acrylate risk assessment with a hybrid computational fluid dynamics and physiologically based nasal dosimetry model.

Cytotoxicity in the nasal epithelium is frequently observed in rodents exposed to volatile organic acids and esters by inhalation. An interspecies, hybrid computational fluid dynamics and physiologically based pharmacokinetic (CFD-PBPK) dosimetry model for inhaled ethyl acrylate (EA) is available for estimating internal dose measures for EA, its metabolite acrylic acid (AA), and EA-mediated reductions in tissue glutathione (GSH). Nasal tissue concentrations of AA were previously used as the dose metric for a chronic Reference Concentration (RfC) calculation with this compound. However, EA was more toxic than expected, based on calculated tissue AA concentrations. Unlike AA, EA causes depletion of tissue GSH. We have developed an RfC for EA using tissue GSH depletion in the olfactory epithelium as the primary measure of nasal tissue dose. The hybrid CFD-PBPK model was refined to improve the accuracy of simulations for GSH in rat olfactory tissues. This refined model was used to determine the concentration for continuous human exposures to EA predicted to reduce nasal GSH levels to the same extent as seen in rats exposed to EA at the no-observed-effect level (NOEL). Importantly, AA concentrations in the human nasal olfactory epithelium at the proposed chronic RfC were predicted to be lower than the AA concentrations estimated in the rat at the NOEL. Thus, a chronic RfC based on maintaining GSH in the human nasal olfactory epithelium at levels equivalent to the rat NOEL would also provide an adequate margin of safety with respect to AA concentrations in nasal tissues.

Acrylates↗

PubMed2004

Evidence that atrazine and diaminochlorotriazine inhibit the estrogen/progesterone induced surge of luteinizing hormone in female Sprague-Dawley rats without changing estrogen receptor action.

High oral doses of atrazine (ATRA) disrupt normal neuroendocrine function, resulting in suppression of the luteinizing hormone (LH) surge in adult, ovariectomized (OVX) estrogen-primed female rats. While the mechanism by which ATRA inhibits LH secretion is not known, current data indicate that ATRA does have anti-estrogenic properties in vitro and in vivo. In the body, ATRA is rapidly converted to diaminochlorotriazine (DACT). The present study was conducted to investigate the effects of ATRA and DACT on the estradiol benzoate (EB)/progesterone (P) induced LH surge and to determine if such changes correlate with impaired estrogen receptor (ER) function. ATRA, administered by gavage for five consecutive days to adult OVX, female Sprague-Dawley rats, caused a dose-dependent suppression of the EB/P induced LH surge. Although to a lesser degree than ATRA, DACT significantly suppressed total plasma LH and peak LH surge levels in EB/P primed animals by 60 and 58%, respectively. DACT treatment also decreased release of LH from the pituitary in response to exogenous gonadotropin releasing hormone (GnRH) by 47% compared to control. Total plasma LH secretion was reduced by 37% compared to control, suggesting that in addition to potential hypothalamic dysfunction, pituitary function is altered. To further investigate the mechanism by which hypothalamic function might be altered, potential anti-estrogenicity of ATRA and DACT were assessed by evaluating ER function treated rats. Using an in vitro receptor binding assay, ATRA, but not DACT, inhibited binding of [(3)H]-estradiol to ER. In contrast, ATRA, administered to female rats under dosing conditions which suppressed the LH surge, neither changed the levels of unoccupied ER nor altered the estrogen induced up-regulation of progesterone receptor mRNA. Collectively, these results indicate that although ATRA is capable of binding ER in vitro, the suppression of LH after treatment with high doses of ATRA is not due to alterations of hypothalamic ER function.

Animals↗

PubMed2004

Induction of CYP1A1 in primary rat hepatocytes by 3,3',4,4',5-pentachlorobiphenyl: evidence for a switch circuit element.

In vivo induction of CYP1A1 in hepatocytes by aryl hydrocarbon receptor agonists is heterogeneous. Using immunohistochemistry, cells appear to be either induced or not induced as if the response of an individual cell is better represented as a switch. We have examined induction of CYP1A1 in vitro in primary rat hepatocytes to distinguish the responses of populations of cells and responses of individual cells. Cells were treated with various concentrations of the aryl hydrocarbon receptor agonist, 3,3',4,4',5-pentachlorobiphenyl. Concentration-response and time-course responses were determined for the population of cells by Western blotting for CYP1A1 protein and by real-time RT-PCR for CYP1A1 mRNA. Individual cell responses were visualized by immunocytochemistry (ICC) for protein and by in situ hybridization (ISH) for mRNA. CYP1A1 mRNA was quantified by frequency distribution analysis of grains observed on the ISH slides. Population responses showed time- and concentration-related increases in induction. Single cell responses appeared as all-or-none in the field, with cells appearing to be induced and others appearing to be not induced. Even at the highest concentrations (2.5 x 10(-7) M), some hepatocytes remained unresponsive. Distribution frequencies of single cell induction were more consistent with a switch with variable levels of induction in cells depending on treatment concentration. Combined with the reports from in vivo studies, our results support a switch with rheostat behavior for individual hepatocytes. Mechanistic studies in liver cell lines that are confirmed to exhibit switch-like induction of single cells will be necessary to assess the molecular pathways of this circuit element.

Animals↗

PubMed2004

Single cell analysis of switch-like induction of CYP1A1 in liver cell lines.

The shape of the dose-response curve may vary depending on whether one examines response at a population or a single cell level. Populations of cells may exhibit a graded response whereas single cell responses may have threshold or switch-like behavior. Studies in vivo and in vitro using primary hepatocyte cultures have shown that induction of CYP1A1 in the liver exhibits switch-like behavior in response to PCB 126 (3,3',4,4',5-pentachlorobiphenyl). The goal of the present study was to determine if two liver cell lines (H4IIE rat hepatoma and Hepa 1c1c7 mouse hepatoma) also show switch-like behavior and develop experimental models for studying mechanisms of these switch-like responses. Both cell lines were analyzed via concentration-response and time-course studies using quantitative real-time PCR, revealing a sigmoidal concentration-response curve for CYP1A1 mRNA induction at the population level. To study CYP1A1 protein induction on a single cell level, flow cytometry was employed. In both cell lines the distribution of fluorescence increased with increasing concentrations of PCB 126. The switch behavior was more pronounced in the H4IIE cells than in the Hepa 1c1c7 cells, exhibiting a well-defined shift of induction from the "off" to the "on" state. The concentration-response curve at the single cell level appeared more switch-like with two populations of cells-basal levels and maximally induced. Immunocytochemistry studies of individual cells also support these conclusions. Our data support the hypothesis that PCB 126 induces CYP1A1 in a switch-like fashion in H4IIE rat hepatoma cells. These cells can now be used to study the mechanism of the biological switch.

Animals↗

PubMed2004

Occupational exposure limits in the context of solvent mixtures, consumption of ethanol, and target tissue dose.

Individuals are exposed to mixtures, and never to single chemicals. Depending on the composition of the elements of mixtures, significant toxicological interactions between the components may occur. These interactions are complex and often difficult to predict, ranging from synergistic to additive and subadditive interactions. The nature of the interactions needs to be evaluated as the target tissue dose of the active form of each chemical. PBPK modeling is an effective tool for determining the target tissue dose and evaluating these interactions when data are available for model development. Some of the interactions are pharmacokinetic in nature, affecting the disposition of other chemicals in the body. Other interactions can be pharmacodynamic in nature, altering the effects that other chemicals have on the organism. For many organic solvents, these interactions occur principally at the level of the metabolizing enzyme, cytochrome P-450 2E1 (CYP2E1). Many solvents are known to induce or inhibit CYP2E1, or both. Mixtures may be comprised of concomitant exposures to chemicals or from components encountered separately on-the-job, off-the-job, through the diet, and otherwise. Examples of mixtures where the exposure to separate components occurs off the job will be discussed, with special emphasis on ethanol consumption as a modifier of solvent pharmacokinetics. The present practice of the linear extrapolation of the toxicity of individual mixture components in the interpretation of occupational exposure limits will also be critiqued.

Alcohol Drinking↗

PubMed2003

Pharmacokinetic modeling of disposition and time-course studies with [14C]atrazine.

A physiological pharmacokinetic (PPK) model, with blood, body, and brain compartments, was developed to estimate total plasma chlorotriazine (CI-TRI) time courses (i.e., atrazine [ATRA] and its three chlorinated metabolites) after oral dosing with ATRA. The model, based on disposition data for 14C-ATRA, tracked two pools of compounds: (1) ATRA and chlorinated metabolites (i.e., the CI-TRIs) and (2) glutathione conjugates. The PPK model developed from total radioactivity was valuable for assessing total plasma CI-TRI concentrations, estimating blood protein binding rates of CI-TRIs, and inferring relationships between tissue exposures of CI-TRIs and administered dose. Absorption of radioactivity into plasma was slow with a rate constant of 0.2 h-1. 14C-disposition data indicated that CI-TRIs react with red blood cells (presumably hemoglobin) and plasma proteins. Second-order rates of reaction of CI-TRIs with hemoglobin and plasma protein were estimated to be 0.008 L/mmol/h and 1.14 x 10(-7) L/mg/h, respectively. A time-course study, conducted as part of this study, evaluated the absorption, disposition, and elimination characteristics of individual CI-TRIs in plasma after a single oral dose of 90 mg ATRA/kg and indicated (1) that slow uptake into blood reflected both absorption and slow dissolution of the ATRA slurry and (2) that diaminochloro-s-triazine (DACT) was the major, persistent plasma CI-TRI after oral dosing. Optimally, PK model development for pesticide compounds like atrazine should include a combination of radiolabeled studies for residues and speciation studies of important metabolites.

Animals↗

PubMed2003

Stochastic simulation of hepatic preneoplastic foci development for four chlorobenzene congeners in a medium-term bioassay.

A combination of experimental and simulation approaches was used to analyze clonal growth of glutathione-S-transferase pi (GST-P) enzyme-altered foci during liver carcinogenesis in an initiation-promotion regimen for 1,4-dichlorobenzene (DCB), 1,2,4,5-tetrachlorobenzene (TECB), pentachlorobenzene (PECB), and hexachlorobenzene (HCB). Male Fisher 344 rats, eight weeks of age, were initiated with a single dose (200 mg/kg, ip) of diethylnitrosamine (DEN). Two weeks later, daily dosing of 0.1 mol/kg chlorobenzene was maintained for six weeks. Partial hepatectomy was performed three weeks after initiation. Liver weight, normal hepatocyte division rates, and the number and volume of GST-P positive foci were obtained at 23, 26, 28, 47, and 56 days after initiation. A clonal growth stochastic model separating the initiated cell population into two distinct subtypes (referred to as A and B cells) was successfully used to describe the foci development data for the four chlorobenzenes. The B cells are initiated cells that display a selective growth advantage under conditions that inhibit the growth of initiated A cells or normal hepatocytes. The simulation exercise for the four chlorobenzenes indicates a positive correlation between the estimated net growth rate of B cells during the 2-week regeneration period following partial hepatectomy and final foci volume at the end of the bioassay. This observation is consistent with the sensitivity analysis of model parameters. While TECB, PECB, and HCB all significantly increased foci volume, only HCB increased normal hepatocyte proliferation. Together, these results indicate that examining effects of chemicals on regenerative responses following partial hepatectomy may be a means for understanding the carcinogenicity potential of chlorobenzene compounds.

Administration, Oral↗

PubMed2003

Toxicokinetic modeling and its applications in chemical risk assessment.

In recent years physiologically based pharmacokinetic (PBPK) modeling has found frequent application in risk assessments where PBPK models serve as important adjuncts to studies on modes of action of xenobiotics. In this regard, studies on mode of action provide insight into both the sites/mechanisms of action and the form of the xenobiotic associated with toxic responses. Validated PBPK models permit calculation of tissue doses of xenobiotics and metabolites for a variety of conditions, i.e. at low-doses, in different animal species, and in different members of a human population. In this manner, these PBPK models support the low-dose and interspecies extrapolations that are important components of current risk assessment methodologies. PBPK models are sometimes referred to as physiological toxicokinetic (PT) models to emphasize their application with compounds causing toxic responses. Pharmacokinetic (PK) modeling in general has a rich history. Data-based PK compartmental models were developed in the 1930's when only primitive tools were available for solving sets of differential equations. These models were expanded in the 1960's and 1970's to accommodate new observations on dose-dependent elimination and flow-limited metabolism. The application of clearance concepts brought many new insights about the disposition of drugs in the body. In the 1970's PBPK/PT models were developed to evaluate metabolism of volatile compounds of occupational importance, and, for the first time, dose-dependent processes in toxicology were included in PBPK models in order to assess the conditions under which saturation of metabolic and elimination processes lead to non-linear dose response relationships. In the 1980's insights from chemical engineers and occupational toxicology were combined to develop PBPK/PT models to support risk assessment with methylene chloride and other solvents. The 1990's witnessed explosive growth in risk assessment applications of PBPK/PT models and in applying sensitivity and variability methods to evaluate model performance. Some of the compounds examined in detail include butadiene, styrene, glycol ethers, dioxins and organic esters/aids. This paper outlines the history of PBPK/PT modeling, emphasizes more recent applications of PBPK/TK models in health risk assessment, and discusses the risk assessment perspective provided by modern uses of these modeling approaches.

Animals↗

PubMed2003

A physiologically based pharmacokinetic model for acrylamide and its metabolite, glycidamide, in the rat.

Acrylamide is a neurotoxicant and a multisite carcinogen in rats following chronic, high-dose exposures. In an effort to improve risk-based decisions for acrylamide (AMD) and its epoxide metabolite, glycidamide (GLY), a physiologically based pharmacokinetic (PBPK) model was developed for describing AMD and GLY kinetics in the rat. The PBPK model consists of components for both AMD and GLY. AMD is distributed within five compartments (arterial blood, venous blood, liver, lung, and all other tissues lumped together) and is linked to the GLY portion of the model via metabolism in the liver. GLY is distributed within the same five compartments. Dosing of AMD via the intravenous, intraperitoneal, or oral route of exposure is incorporated into the model structure. The model parameters include measured values for rat physiology (tissue volumes, blood flows), estimated tissue partition coefficients based on a published algorithm, and estimated values for metabolism and tissue binding based on fitting the model to tissue kinetic data from four studies. Despite gaps and limitations in the available database, a reliable description of the kinetics of AMD and GLY from existing studies was obtained using a single set of model parameters. The metabolism of AMD via cytochrome P-450 was best described using a Vmax of 1.6 mg/h/kg and a Km of 10 mg/L, while the metabolism of AMD via GST was described using a second-order rate constant of 0.55 L/h-mmol GSH. Similarly, the metabolism of GLY via epoxide hydrolase was best described using a Vmax of 1.9 mg/h/kg and a Km of 100 mg/L, while the metabolism of GLY via GST was described using a rate constant of 0.8 L/h-mmol GSH. These parameters were established based on the proportion of various metabolites found in urine. Future studies will need to focus on the collection of key data for refining model parameters for metabolism and tissue binding and for model validation, as well as for developing a similar model for humans. Completion of these additional studies will result in a validated rat and human PBPK model capable of predicting tissue doses linked to potential mechanisms of toxic effects for AMD and GLY and allow determination of scientifically defensible exposure limits that remain protective of human health.

Acrylamide↗

PubMed2003

Closed-chamber inhalation pharmacokinetic studies with hexamethyldisiloxane in the rat.

Gas uptake methods together with physiologically based pharmacokinetic (PBPK) modeling have been used to assess metabolic parameters and oral absorption rates for a wide variety of volatile organic compounds. We applied these techniques to study the in vivo metabolism of hexamethyldisiloxane (HMDS), a volatile siloxane with low blood/air (partition coefficient PB approximately 1.00) and high fat/blood partitioning (partition coefficient PF approximately 300). In contrast to other classes of metabolized volatiles, metabolic parameters could only be estimated from closed-chamber results with confidence by evaluating both closed-chamber disappearance curves and constant concentration inhalation studies. The constant-concentration inhalation results refine the estimate of the blood/air partition coefficient and constrain model structure for storage of the lipophilic compound in blood and tissues. The gas uptake results, from Fischer 344 rats (male, 8-9 wk old) exposed to initial HMDS air concentrations from 500 to 5000 ppm, were modeled with a 5-tissue PBPK model. Excellent fits were obtained with diffusion-limited uptake of HMDS in fat and a lipid storage pool in the blood. Metabolism, restricted to the liver, was described as a single saturable process (V(max) = 113.6 micro mol/h/kg; K(m) = 42.6 micro mol/L) and was affected by inhibitors (diethyldithiocarbamate) or inducers (phenobarbital) of cytochrome P-450s. Exhalation kinetics of HMDS after oral/intraperitoneal administration showed low bioavailability and significant lag times, also quite different from results of other classes of volatile hydrocarbons. In general, estimates of metabolic clearance by gas uptake studies were improved by simultaneous examination of time-course results from constant concentration inhalation studies. This conclusion is likely to hold for any volatile lipophilic compound with low blood/air partitioning.

Adipose Tissue↗

PubMed2003

Characterization of the pharmacokinetics of gasoline using PBPK modeling with a complex mixtures chemical lumping approach.

Gasoline consists of a few toxicologically significant components and a large number of other hydrocarbons in a complex mixture. By using an integrated, physiologically based pharmacokinetic (PBPK) modeling and lumping approach, we have developed a method for characterizing the pharmacokinetics (PKs) of gasoline in rats. The PBPK model tracks selected target components (benzene, toluene, ethylbenzene, o-xylene [BTEX], and n-hexane) and a lumped chemical group representing all nontarget components, with competitive metabolic inhibition between all target compounds and the lumped chemical. PK data was acquired by performing gas uptake PK studies with male F344 rats in a closed chamber. Chamber air samples were analyzed every 10-20 min by gas chromatography/flame ionization detection and all nontarget chemicals were co-integrated. A four-compartment PBPK model with metabolic interactions was constructed using the BTEX, n-hexane, and lumped chemical data. Target chemical kinetic parameters were refined by studies with either the single chemical alone or with all five chemicals together. o-Xylene, at high concentrations, decreased alveolar ventilation, consistent with respiratory irritation. A six-chemical interaction model with the lumped chemical group was used to estimate lumped chemical partitioning and metabolic parameters for a winter blend of gasoline with methyl t-butyl ether and a summer blend without any oxygenate. Computer simulation results from this model matched well with experimental data from single chemical, five-chemical mixture, and the two blends of gasoline. The PBPK model analysis indicated that metabolism of individual components was inhibited up to 27% during the 6-h gas uptake experiments of gasoline exposures.

Animals↗

PubMed2003

Route-specific differences in distribution characteristics of octamethylcyclotetrasiloxane in rats: analysis using PBPK models.

Octamethylcyclotetrasiloxane (D(4)) is used in selected consumer products and has a potential for human exposure from multiple routes. Here we develop a physiologically based pharmacokinetic (PBPK) model to describe the tissue dosimetry, plasma concentration, and clearance in the rat following inhalation and dermal, oral, and iv exposure. An initial multiroute PBPK model, based on a previously published inhalation PBPK model for D(4), provided excellent fits to the observed concentration time course of D(4) metabolites in urine and D(4) exhalation rate following dermal exposures. However, the pharmacokinetics of D(4), following oral and iv exposure, were sensitive to the mode of entry into the blood compartment. A refined model, describing delivery of D(4) from the GI tract to the nonexchangeable/deep blood compartment, provided the best fits to observed plasma D(4), exhaled D(4), and D(4) metabolites excreted in the urine following oral exposure. Pharmacokinetics following iv administration was best described by delivery of D(4) directly into the deep blood compartment, possibly reflecting a kinetically identifiable characteristic of the administration of D(4) as an emulsion for the intravenous route of exposure. This model-based analysis indicates that the pharmacokinetics of D(4) delivered by the inhalation or dermal routes is similar, and is different from the iv or oral delivery routes.

Adjuvants, Immunologic↗